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Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 2177-2181
Involvement of Donor T-Cell Cytotoxic Effector Mechanisms in
Preventing Allogeneic Marrow Graft Rejection
By
Paul J. Martin,
Yoshiki Akatsuka,
Michael Hahne, and
George Sale
From the Division of Clinical Research, the Fred Hutchinson Cancer
Research Center, Seattle, WA; the Departments of Medicine and
Pathology, University of Washington, Seattle, WA; and the Institute of
Biochemistry, University of Lausanne, Epalinges, Switzerland.
 |
ABSTRACT |
Donor CD8 cells play a pivotal role in preventing allogeneic marrow
graft rejection, possibly by generating cytotoxic effectors needed to
eliminate recipient T cells remaining after the pretransplant conditioning regimen or by producing cytokines needed to support the
growth and differentiation of hematopoietic stem cells. In the present
study, we assessed the role of donor T-cell cytotoxic effector function
as a mechanism for eliminating recipient CD8 cells that cause marrow
graft rejection in mice. The ability to prevent rejection was minimally
affected by the presence of a defect in Fas ligand binding or by the
absence of granzyme B but was severely affected by the absence of
perforin. Doubly mutant perforin-deficient, Fas ligand-defective CD8
cells were completely unable to prevent rejection. Our results indicate
first that recipient CD8 effectors responsible for causing marrow graft
rejection are sensitive to cytotoxicity mediated by both perforin- and
Fas-ligand-dependent mechanisms, and second that donor T cells must
have at least one functional cytotoxic mechanism to prevent allogeneic
marrow graft rejection.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
DONOR CD8 CELLS PLAY a pivotal role in
preventing allogeneic marrow graft rejection in mice and are
substantially more effective than donor CD4 cells.1 Based
on the known function and specificity of CD8 cells and CD4 cells in
primary allospecific T-cell populations,2 we suggested that
the generation of T- cytotoxic responses against major
histocompatibility complex (MHC) class I alloantigens or class
I-restricted peptides was the most likely mechanism by
which donor T cells inactivate or eliminate the recipient effectors responsible for causing rejection. This hypothesis was supported by
results demonstrating that T cells from nontolerant donors were more
effective for preventing rejection than T cells from F13 or
chimeric donors4 that could not recognize recipient
alloantigens.
We have now assessed the role of cytotoxic effector function as a
mechanism by which donor T cells might prevent allogeneic marrow graft
rejection. The cytotoxic effector function of T lymphocytes can be
mediated by two well-characterized mechanisms.5-7 One of
these involves cell surface interactions between Fas ligand expressed
on activated cytotoxic lymphocytes (CTL) and Fas expressed on target cells. The other involves granule exocytosis, a process in
which perforin facilitates the translocation of granzymes from CTL into
target cells. Both mechanisms induce apoptosis in target cells.
Additional less well-characterized mechanisms are involved in cytolytic
effector function against certain types of target cells.8
In the present study, we evaluated the effect of mutations in the
Fas-ligand and perforin/granzyme pathways on the ability of donor CD8
cells to prevent allogeneic marrow graft rejection caused by recipient
CD8 cells. In further experiments, we evaluated the ability of Fas
ligand-defective perforin-deficient T cells to cause graft-versus-host
disease (GVHD).
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MATERIALS AND METHODS |
Mice.
C57BL/6J (B6; H2b, Ly5.2) males,
B6.C-H2bm1 (bm1; Ly5.2) males and females, and
BALB/cJ (H2d) females were purchased from the Jackson
Laboratory (Bar Harbor, ME). Founders for the Ly5-congenic
B6.SJL-Ly5a Ptprca Pep3b
(B6-Ly5.1) strain (provided by Dr David Myers, Sloan Kettering Institute, New York, NY) and for Fas ligand-defective
B6Smn.C3H-Faslgld (gld), granzyme
B-deficient B6, 129-Gzmbtm1Ley9 and
perforin-deficient C57BL/6-Pfptm1Sdz10 strains
(purchased from the Jackson Laboratory) were bred at the Fred
Hutchinson Cancer Research Center (FHCRC; Seattle, WA). Perforin-deficient, gld-homozygous founder males10
(provided by Prof Jurg Tschopp, Institute of Biochemistry,
University of Lausanne, Epalinges, Switzerland) were backcrossed to
gld females, and the offspring were intercrossed to generate
perforin-deficient gld progeny. In these mice, the neo
cassette that disrupts perforin expression is inserted at the exon 3 SphI site.11 Perforin-deficient, gld-homozygous
mice were also generated by intercrossing the offspring from mating
(gld × C57BL/6-Pfptm1Sdz) F1 males
with C57BL/6-Pfptm1Sdz females. In these mice,
the neo cassette that disrupts perforin expression is inserted
at the exon 3 BstEII site.10 Mice were housed in
groups of 5 under specific pathogen-free conditions with twice weekly
cage changes and received sterilized chow and acidified water (pH 3.5)
ad libitum. Four weeks after marrow transplantation, mice were
transferred to conventional housing conditions. Experiments were
reviewed and approved by the Institutional Animal Care and Use
Committee of the FHCRC.
Screening for gld and perforin mutations.
For detection of gld and wild-type Fasl alleles,
peripheral blood leukocyte (PBL) DNA was amplified
respectively with 5 primer TTTGAGGAATCTAAGACCC or TTTGAGGAATCTAAGACCT
and 3 primer ATAGCTGACCTGTTGGACC (94°C for 4 minutes, followed by
30 seconds at 94°C, 30 seconds at 58°C, and 45 seconds at
72°C for 35 cycles with 1.5 mmol/L MgCl2, 200 µmol/L
dNTP, and 0.5 U Taq polymerase; AmpliTaq Gold; Perkin Elmer, Foster
City, CA), each yielding a 200-bp product. For detection of neo
insertions at the perforin exon 3 Sph I site11 and
BstEII site,10 PBL DNA was amplified, respectively,
with 5 primer ACCTCCACTCCACCTTGA and 3 primer GATAAAGTGCGTGCCATAG or
with 5 primer AGTGTGAGTGCCAGGATTC and 3 primer CGGGGATTGTTATTGTTC (94°C for 9 minutes, followed by 30 seconds at 94°C, 30 seconds at 60°C, and 90 seconds at 72°C for 35 cycles with 1.5 mmol/L MgCl2, 500 µmol/L dNTP, and 1.0 U Taq polymerase). The
wild-type alleles, respectively, yield 115- and 199-bp products,
whereas the mutated alleles yield 1,100- to 1,200-bp products.
Marrow transplantation.
Recipients 8 to 12 weeks of age were prepared by total body irradiation
(TBI) in a single fraction from dual-opposed
60Co sources at an exposure rate of 20 cGy/min on the day
before transplantation. Marrow obtained by femur flush was depleted of T lymphocytes by rabbit complement (1:10)-mediated lysis using a
mixture of antibodies specific for Thy-1.2, CD4, and CD8, as previously
described.1 Nylon wool-nonadherent lymphocytes obtained from pooled mesenteric, retroperitoneal, femoral, axillary, and cervical lymph node suspensions were depleted of B cells by centrifugal immunoadherence12 on plastic petri dishes precoated with
goat antibody against mouse Ig (10 µg/mL in pH 9.4 buffer, 18 hours at 4°C) or with CD45R/B220-specific antibody RA3-6B2 (rat IgG2a; PharMingen, San Diego, CA) or RA3-3A1/6.1 (rat IgM; hybridoma obtained
from American Type Culture Collection [ATCC], Rockville, MD; 12.5 µg/mL bound to dishes coated with goat antibody against rat Ig).
CD8-enriched T cells were isolated either by centrifugal immunoadherent
depletion of CD4 cells on dishes precoated with antibody GK1.5 (rat
IgG2b; ATCC; antibody from hybridoma culture supernatant bound to
dishes coated with goat antibody against rat Ig) or by immunomagnetic
positive selection with colloidal superparamagnetic microbeads
conjugated with monoclonal rat antibody against murine CD8 (Miltenyi
Biotec Inc, Sunnyvale, CA) used according to the manufacturer's
instructions. CD8-enriched populations isolated by negative selection
contained 82% to 94% (mean, 88.5%) CD8 cells and 1.0% to 2.4%
(mean, 1.5%) CD4 cells. CD8-enriched populations isolated by positive
selection contained 83% to 96% (mean, 90.7%) CD8 cells and 3.8% to
10.6% (mean, 7.1%) CD4 cells. For experiments in which engraftment
was an endpoint, graded numbers of CD8-enriched LN cells were added to
grafts containing 5.0 × 106 T-cell-depleted marrow
cells. For experiments in which GVHD was an endpoint, aliquots
containing 1.0 × 107 CD3 cells from pooled nylon
wool- nonadherent spleen and lymph node suspensions were added to
grafts containing 40 × 106 T-cell-depleted marrow
cells. Cell mixtures were injected into recipients via the lateral tail
vein.
Assessment of chimerism and enumeration of peripheral blood B cells.
PBL were stained with fluorescein isothiocyanate
(FITC)-conjugated CD3-specific antibody and with
biotinylated antibody specific for Ly5.1 or H2Kb and
analyzed as previously described.1 For each experiment, thresholds for delineating positive and negative cells were determined by staining samples from appropriate positive and negative controls. In
the T-cell and myeloid gates, respectively, negative control samples
showed 0.15% to 1.56% (mean, 0.65%) and 0.56% to 14.0% (mean,
2.5%) background staining, whereas positive control samples showed
97.6% to 100% (mean, 99.3%) and 93.1% to 100% (mean, 98.0%) stained cells. For enumeration of B cells, PBL were stained with FITC-conjugated CD3-specific antibody and biotinylated antibody specific for CD45RA (14.8, rat IgG2b; hybridoma obtained from ATCC) or
with phycoerythrin (PE)-conjugated CD3-specific antibody (PharMingen) and FITC-conjugated CD45R/B220-specific antibody (PharMingen). B cells were enumerated as the percentage of
CD45RA+ or CD45R+, CD3 cells in
the lymphoid gate defined by forward and side scatter characteristics.
| |
RESULTS |
Ability of donor CD8 cells to prevent marrow graft rejection.
Preliminary experiments demonstrated that TBI exposures  650 cGy were
sufficient to prevent rejection in bm1 (Ly5.2) recipients transplanted
with 5.0 × 106 T-cell-depleted marrow cells from MHC
class I-disparate B6-Ly5.1 donors, but rejection occurred in recipients
prepared with 550 cGy TBI (data not shown). The ability to overcome
rejection by increased pretransplant TBI in this model is
characteristic of a process mediated by T cells1,4 and not
by natural killer (NK) cells13,14 of the
recipient. Rejection of the B6-Ly5.1 marrow was prevented in some
recipients prepared with 550 cGy TBI when as few as 5.0 × 104 CD8-enriched B6 (Ly5.2) LN cells were added
to the graft, and rejection was prevented in all recipients when 8.0 × 105 CD8 cells were added to the graft
(Table 1). Under these conditions, engraftment of the donor marrow depends on the presence of T cells in
the graft. In most engrafted recipients, T cells in the blood on day 28 after transplantation were derived predominantly from Ly5.1 marrow
progenitors and not from mature Ly5.2 LN cells added to the graft, and
the proportion of donor marrow-derived T cells increased progressively
during the first 3 months after transplantation. Thus, the B6 CD8 cells
added to the graft did not prevent maturation of B6-Ly5.1 marrow
progenitors in the bm1 recipient thymus.
Effect of cytotoxicity mutations on the ability of donor T cells to
prevent marrow graft rejection.
In a series of seven experiments, we evaluated the effect of mutations
in the Fas-ligand and perforin/granzyme pathways on the ability of
donor CD8 cells to prevent rejection of B6-Ly5.1 marrow in irradiated
bm1 recipients. Each experiment included negative controls with no
donor T cells added to the marrow and positive controls with wild-type
B6 CD8-enriched LN T cells added to the graft. In this model,
approximately 1.0 × 105 wild-type B6 CD8 cells
prevent rejection in 50% of the recipients (Table 2). The defect in
Fas-ligand-mediated cytotoxicity caused by the gld mutation had
only a minimal effect on the ability of donor T cells to prevent
rejection. Although rejection occurred in all 15 recipients
transplanted with grafts containing 5.0 × 104 CD8
cells enriched by negative selection (P  .01 compared with wild-type B6 CD8 cells), rejection was prevented in all recipients transplanted with grafts containing 2.0 × 105 or
8.0 × 105 gld CD8 cells. The
absence of granzyme B in donor CD8 cells also had a minimal effect on
their ability to prevent rejection. Although rejection occurred in all
14 recipients transplanted with grafts containing 5.0 × 104 CD8 cells enriched by negative selection (P .02 compared with wild-type B6 CD8 cells), rejection was prevented in 9 of 10 recipients transplanted with grafts containing 2.0 × 105 or 8.0 × 105 granzyme
B-deficient CD8 cells.
Perforin-deficient donor CD8 cells were clearly impaired in their
ability to prevent rejection. Results indicated that 2 to 3 × 106 perforin-deficient CD8 cells enriched by positive or
negative selection were needed to prevent rejection in 50% of
recipients. With 1.0 × 107 positively selected
perforin-deficient CD8 cells added to the graft, rejection was
prevented in all recipients. These results demonstrate that
perforin-deficient CD8 cells have approximately 3% to 5% of wild-type
activity in preventing marrow graft rejection in this model.
Prevention of marrow graft rejection by donor CD8 cells was tested with
two strains having defects in both the Fas ligand and perforin pathways
of cytotoxicity. Rejection was not prevented by as many as 2.0 × 107 positively selected CD8 cells from doubly mutant donors
with perforin expression disrupted by an insertion at the exon 3 Sph I site. Because this perforin-deficient strain was
backcrossed to B6 for 8 to 10 generations, graft failure could have
been caused through recognition of the donor B6-Ly5.1 marrow by the
mutant T cells and not through failure to prevent rejection by the bm1 recipient. This issue was addressed in two ways. First, heavily irradiated (950 cGy) bm1 recipients were transplanted with grafts containing 5.0 × 106 T-cell-depleted B6-Ly5.1 marrow
cells alone (n = 4) or with 1.0 × 107 CD8-
enriched LN cells from (Sph I) perforin-deficient
gld-homozygous donors added to the graft (n = 2). All
recipients survived and were engrafted with Ly5.1-positive cells when
tested at 28 and 61 days after transplantation (data not shown). These
results demonstrate that rejection of the B6-Ly5.1 marrow in 550-cGy
irradiated bm1 recipients could not have been caused by mutant T cells
added to the graft. In a further experiment, we tested CD8 cells from doubly mutant donors generated from a perforin-deficient strain that
was fully backcrossed to B6. Rejection was not prevented by 1.0 × 107 positively selected CD8 cells from doubly mutant donors
with perforin expression disrupted by an insertion at the exon 3 BstEII site (Table 2). Taken together, these results
demonstrate that the doubly mutant T cells had less than 1% of
wild-type activity in preventing marrow graft rejection in this model.
Ability of T cells with cytotoxicity mutations to cause GVHD.
Results of a previous study showed that T cells from donors with
defects in both the Fas ligand and perforin pathways of cytotoxicity did not cause GVHD in sublethally irradiated recipients.8
Our new findings demonstrating that donor T-cell-mediated cytotoxicity is necessary to prevent marrow graft rejection in sublethally irradiated recipients suggested that the absence of GVHD in the previous study could be explained by the lack of engraftment. Therefore, it was of interest to determine whether doubly mutant T
cells could cause GVHD under conditions in which engraftment did not
depend on the cytotoxic activity of these cells. For these experiments,
lethally irradiated (1,100 cGy) BALB/c recipients were transplanted
with 40 × 106 T-cell-depleted B6 or B6-Ly5.1 marrow
cells alone or with 1.0 × 107 CD3 cells from doubly
mutant donors added to the graft. All recipients were engrafted with
donor cells, as demonstrated by H2 typing at 1 and 2 months after
transplantation (data not shown). In each of three experiments, the
perforin-deficient, Fas-ligand-defective T cells caused GVHD, as
indicated by weight loss and B lymphopenia as compared with negative
control recipients transplanted with marrow alone
(Table 3). However, histopathologic
examination of the skin, liver, gastrointestinal tract, and lungs with
blinding of treatment groups showed no differences between mice
transplanted with grafts containing mutant T cells and those
transplanted with marrow alone. Recipients transplanted with grafts
containing doubly mutant T cells did not have lymphadenopathy at the
time of autopsy.
| |
DISCUSSION |
Results of the current study demonstrate that cytotoxicity mediated by
either perforin- or Fas ligand-dependent mechanisms is necessary for
enabling donor T cells to prevent allogeneic marrow graft rejection.
Previous studies have shown that rejection of H-2K-disparate marrow is
caused by recipient CD8 effectors that survive the pretransplant
conditioning regimen.15 Our current results therefore
indicate that these cells are sensitive to cytotoxicity mediated by
both perforin or Fas ligand-dependent mechanisms. These results are
consistent with observations that ConA blasts are sensitive to lysis by
either mechanism but are not lysed by CTL in short-term (4 hours)
assays when both mechanisms were absent.7,8 Even though
activated CD8 cells are sensitive to apoptosis induced by ligation of
TNFp75 receptors under certain conditions,16 cytokine-mediated mechanisms are not sufficient for the elimination of
recipient CD8 cells that cause marrow graft rejection.
Comparison of results with Fas-ligand defective CD8 cells and
perforin-deficient CD8 cells suggests that the ability of donor T cells
to prevent marrow graft rejection depends predominantly on
perforin-dependent mechanisms of cytotoxicity. The striking difference
in results between granzyme B-deficient and perforin- deficient T cells
confirms that granzyme B is not essential for granule exocytosis
mechanisms of cytotoxicity.17 In the absence of perforin,
large numbers of donor CD8 cells were needed in order to prevent
rejection, whereas Fas-ligand-defective CD8 cells were minimally
impaired in their ability to prevent rejection. The relative importance
of the perforin pathway as compared with the Fas-ligand pathway in
cytotoxicity against T-cell targets has been demonstrated previously.
Braun et al8 showed that sublethally irradiated
perforin-deficient H2b recipients could not reject
allogeneic H2d BALB/c spleen cell grafts and were therefore
susceptible to lethal acute GVHD, whereas identically treated
Fas-ligand-defective recipients did not develop GVHD, suggesting that
the ability to prevent allogeneic T-cell engraftment was not impaired.
These results are consistent with in vitro observations that the
absence of Fas on ConA blast targets has limited effects on their
susceptibility to lysis by CTL.7,8
Baker et al18 have reported contrary results in experiments
with B6 donors and lethally irradiated H2- compatible C3H.SW recipients. In their experiments, readily detectable numbers of host-derived myeloid cells, B lymphocytes, and thymocytes remained in
recipients transplanted with grafts containing Fas-ligand-defective T
cells, but few, if any, such host-derived cells were found in identically treated recipients transplanted with grafts containing perforin-deficient T cells. These results suggested that
Fas-ligand-dependent mechanisms of cytotoxicity were predominantly
responsible for eliminating recipient hematopoietic progenitors that
survived the pretransplant conditioning regimen.
At least two explanations can be invoked to account for the differences
in results among these studies. First, the targets killed by cytotoxic
effectors were not identical in the two studies. T cells of the
recipient or donor were the targets evaluated in our experiments,
whereas hematopoietic progenitors of the recipient were the targets
evaluated by Baker et al.18 Thus, T cells might be less
susceptible to Fas-ligand-mediated cytotoxicity or more susceptible to
perforin-mediated cytotoxicity as compared with hematopoietic
progenitors. Second, the effectors evaluated in the two studies might
not be identical. Although we have tested LN CD8 cells, the effectors
responsible for elimination of recipient cells in the H2-identical B6
 C3H.SW transplant model have not been identified. If the
minor histocompatibility antigens that cause GVHD in this model are
presented by MHC-class II molecules, the effectors could be CD4 cells.
This suggestion is consistent with observations that CD4 cells mediate
cytotoxicity through Fas-ligand-dependent mechanisms and not through
perforin-dependent mechanisms.19-21
The availability of murine strains with induced mutations has
facilitated considerable progress in dissecting the effector mechanisms
contributing to GVHD.8,18,22 Previous studies have shown
that perforin-deficient T cells have a decreased ability to induce GVHD
as measured by the number of donor T cells required to cause mortality
in recipients with disparity for major or minor histocompatibility
antigens.8,22 Recipients transplanted with Fas-ligand-defective T cells from gld donors developed
cachexia, but inflammatory lesions in the skin and liver were absent,
and the profound B-lymphoid hypoplasia typically associated with GVHD did not occur.22 Our current results
highlight the role of cytokine-mediated mechanisms by demonstrating
that GVHD can occur in the absence of Fas-ligand- and perforin-mediated
cytotoxicity. On the other hand, with a sufficient number of donor
cells, lethal GVHD can also occur in the absence of signals transduced
by ligation of TNFp55 receptors.23 Taken together, these
results suggest that GVHD can develop both through cell-mediated
cytotoxicity and through cytokine-mediated mechanisms. Our results
confirm the earlier report by Baker et al,22 who showed
that inflammatory cell infiltrates and apoptotic epithelial damage are
not prominent in the liver and skin when GVHD is caused by cells that
lack Fas-ligand.
Our current results demonstrating the importance of perforin-mediated
cytotoxicity as a mechanism enabling donor T cells to prevent
allogeneic marrow graft rejection suggest possible approaches for
future clinical trials. Recent studies have shown that cytotoxic CD8
cells can have either a type 1 or type 2 cytokine
profile.24,25 Type 1 polarized CD8 cells mediate
cytotoxicity through either Fas-ligand or perforin-dependent
mechanisms, whereas type 2 polarized CD8 cells rely predominantly on
perforin-dependent mechanisms.26 Type 2 polarized CD8 cells
also have a reduced ability to cause GVHD as compared with type 1 polarized cells.27,28 Taken together, these results suggest
that retention of type 2 polarized donor CD8 cells in the graft could
avoid marrow graft rejection when T-cell depletion is used to prevent
GVHD.
| |
FOOTNOTES |
Submitted March 31, 1998;
accepted May 6, 1998.
Supported by US Public Health Service Grant No. HL-55257 awarded by the
Department of Health and Human Services, National Institutes of Health.
Address correspondence to Paul J. Martin, MD, Fred Hutchinson Cancer
Research Center, 1100 Fairview Ave N, D2-100, Seattle, WA 98109-1024;
e-mail: pmartin{at}fhcrc.org.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Kelli McIntyre and Natasha Leman for technical
assistance and animal husbandry, Dr Wendy Leisenring for statistical
consultation, Drs Ilonna Rimm and Claudio Anasetti for critical reading
of the manuscript, and Alison Sell for assistance in preparing the
manuscript.
| |
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Abstract
Introduction
Abstract